Head and neck squamous cell carcinoma (HNSCC) affects nearly 40,000 new patients each year. Despite advances in therapy mortality rates from HNSCC remain high due to the development of metastases and therapy resistance. Tumor hypoxia is an important factor that determines the response of head and neck squamous cell carcinomas to surgery, chemotherapy and radiation treatment and is associated with worse clinical outcome. Such adaptations to therapy are linked in part to the ability of hypoxic tumor cells to slowdown cell cycle progression or enter a growth arrest/quiescent mode. However whether the therapy resistance is merely due to the lack of proliferation or whether these cells can tap into pathways that can coordinate the cell- cycle arrest program to the upregulation of survival programs needs to be elucidated. One such pathway that is induced during tumor hypoxia and can activate growth arrest and survival in a concerted manner is the endoplasmic reticulum (ER) stress response. In studying a human HNSCC cell line (T-HEp3) that is tumorigenic and metastatic in vivo, we found that activation of p38 signaling induces G0/G1 arrest and dormant phenotype in vivo. Further these dormant HEp3 (D-HEp3) cells also displayed a p38-dependent increases in the ER stress markers BiP/grp78 and PERK signaling. While both BiP and PERK promoted resistance to chemotherapeutic drug-induced apoptosis, only PERK activation contributed to the in vivo growth arrest/quiescence program. While the cytoprotective functions of BiP and PERK are known to promote tumor cell survival in vivo during hypoxia, whether the concurrent induction of PERK mediated quiescence is part of this adaptive mechanism need to be elucidated. We propose that similar to D-HEp3 cells, tumor cells within the hypoxic milieu of a growing tumor induce BiP and PERK regulated survival and growth arrest programs to promote therapy-resistance. A growing body of evidence suggests that tumor initiating cells (TICs) in addition to propagating tumor growth, can also resist standard therapy regimens. It is therefore vital to identify mechanisms that specifically enable them to survive stress insults (chemo and radiotherapy) that can otherwise debulk most of the cancer cells. We have identified a TIC subpopulation that can not only drive the in vivo tumor growth in T-HEp3 cells but could also adopt a dormant behavior in response to stress. We hypothesize that TICs residing in the hypoxic regions of tumors rely on BiP and PERK mediated survival and quiescence programs to resist therapy and that unlike majority of the tumor cells, TICs can activate a faster ER stress recovery mechanism that enables them to reverse PERK induced quiescence and resume growth. We propose to examine (i) the mechanisms of BiP mediated therapy resistance in hypoxic tumor cells and (ii) whether PERK initiated survival and quiescence programs drive treatment resistance of hypoxic tumor cells. We will also determine if this quiescence program is differentially regulated between TICs vs non-TICs. Public Health Relevance: We will explore whether ER stress signaling promotes therapy resistance by concomitantly activating survival and quiescence programs. Therapy resistance of hypoxic tumor cells is one of the major factors for the poor survival rates among head and neck cancer patients. The targets of this study will enable us to tailor novel combinatorial treatments that would sensitize the otherwise therapy insensitive quiescent hypoxic tumor cells to traditional therapeutics.